Chroman derivatives

ABSTRACT

Derivatives of trans-3-hydroxy-4-amino-chroman and pharmaceutical compositions containing such derivatives are useful for effecting vasodilation in mammals, including humans.

CROSS-REFERENCE

This is a division of Ser. No. 577,614 filed May 14, 1975, now U.S. Pat. No. 4,048,317.

The present invention relates to chroman derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

More specifically, this invention relates to derivatives of trans-3-hydroxy-4-amino-chroman which possess blood pressure lowering activity, to their preparation by the reaction of amines on chroman epoxide derivatives and to pharmaceutical compositions containing the compounds of the invention which may be used in the treatment of hypertension in mammals including humans.

The compounds according to this invention are of the formula (I): ##STR1## and acid addition salts thereof wherein R₁ is a hydrogen atom or a C₁₋₉ hydrocarbon group optionally substituted by a hydroxyl or C₁₋₆ alkoxyl group; R₂ is a hydrogen atom or C₁₋₆ alkyl group, or NR₁ R₂ is a 3- 8 membered heterocyclic group optionally substituted by one or two methyl groups; R₃ is a hydrogen or halogen atom or a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkoxyl, C₂₋₆ alkenoxyl, C₁₋₆ alkylthio, hydroxyl, amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, nitro, trifluoromethyl, C₂₋₇ acylamino, C₁₋₆ alkoxysulphonylamino, carboxyl, nitrile or AOR₇, ASR₇, ASO₂ R₇, ANHR₇, ANR₇ COR₈, ANR₇ SO₂ R₈ or ANR₇ CO₂ R₈ group wherein A is an alkylene group of 1- 4 carbon atoms, R₇ is an alkyl group of 1- 4 carbon atoms and R₈ is an alkyl group of 1- 4 carbon atoms; R₄ is a hydrogen or halogen atom or methyl or methoxy, or R₃ together with R₄ forms a --CH ═ CH -- CH ═ CH --, --NH -- CH ═ CH--, --CH₂ --CH₂ --CH₂ --CH₂ -- or --CH₂ --CH₂ --CH₂ --CO-- system; R₅ is a hydrogen atom or a C₁₋₆ alkyl or phenyl group; and R₆ is a hydrogen atom or a C₁₋₆ alkyl or phenyl group.

Suitable groups R₁ include the hydrogen atom and the methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, allyl, phenyl, benzyl, tolyl, cyclopropylmethyl, cyclohexyl and the like groups.

Particularly suitable groups R₁ include C₁₋₆ alkyl groups.

Suitable groups R₂ include the hydrogen atom and the methyl, ethyl, propyl and like groups.

Suitable heterocyclic groups NR₁ R₂ include the pyrrolidyl, piperidyl, morpholino, methylpyrrolidyl, N-methylpiperazine, hexamethyleneamino, N-phenylpiperazine, hexamethylenetetramine and the like groups.

Especially suitable groups R₅ and R₆ include the methyl and ethyl groups.

Preferred groups R₅ and R₆ include the methyl group.

Particularly suitable compounds of the formula (I) wherein R₄ is a hydrogen atom include those of the formula (II): ##STR2## and their salts wherein R₃ is as defined in relation to formula (I), R₉ is a methyl or ethyl group, R₁₀ is a methyl or ethyl group and either (a), NR₁ R₂ is a group NR₁₁ R₁₂ wherein R₁₁ is an alkyl group of 1-4 carbon atoms and R₁₂ is a hydrogen atom or a methyl or ethyl group or (b) NR₁ R₂ is a group of the sub-formula: ##STR3## wherein X is a bond joining the two carbon atoms or is a CH₂, CH₂.CH₂, CH₂.CH₂.CH₂, CH:CH, O, S or NCH₃ group, R₁₃ is a hydrogen atom or a methyl group and R₁₄ is a hydrogen atom or a methyl group.

Most suitably, NR₁₁ R₁₂ is a N(CH₃)₂ or NH C₁₋₄ alkyl group.

Most suitably X is a bond or a CH₂ or CH₂ CH₂ group.

Particularly suitable groups R₃ for inclusion in compounds of the formula (I) or (II) include the allyl, allyloxy, nitro, trifluoromethyl, nitrile, NH.CO.R₁₆, NHSO₂ R₁₆, NHSO₃ R₁₆, (CH₂)_(n) OR₁₆ or (CH₂)_(n) NH.CO.R₁₆ where R₁₆ is an alkyl group of 1-4 carbon atoms and n is 1, 2 or 3.

A further particularly suitable group of compounds of the formula (I) is that of the formula (III): ##STR4## and salts thereof wherein NR₁ R₂, R₉ and R₁₀ are as defined in relation to formula (II).

Particularly suitable groups NR₁ R₂ in compounds of formulae (I), (II) or (III) include NHC(CH₃)₃, NH.CH(CH₃)₂, pyrrolidyl and piperidyl groups.

Particularly suitable groups R₅, R₆, R₉ and R₁₀ for inclusion in compounds of formulae (I), (II) or (III) include the methyl group.

One suitable sub-group of the compounds of formula (I) are those of formula (IV): ##STR5## and salts thereof wherein R₁₈ is a C₁₋₆ alkyl, phenyl or benzyl group and R₃ and R₄ are as defined in relation to formula (I).

Most suitably R₁₈ is an iso-propyl, iso-butyl or t-butyl group.

A further sub-group of the compounds of formula (I) worthy of mention are those of formula (V): ##STR6## and salts thereof wherein R₃ and R₄ are as defined in relation to formula (I).

Suitable groups R₃ for inclusion in the compounds of formulae (II), (IV) or (V) include the hydrogen, fluorine, chlorine and bromine atoms and the methyl, ethyl, propyl, allyl, trifluoromethyl, methoxyl, methylthio, hydroxyl, nitro, allyloxyl, amino, acetamido, methoxysulphonylamino and the like groups.

Suitable groups R₄ for inclusion in the compounds of formulae (I), (IV) or (V) include the hydrogen, fluorine and chlorine atoms and the methyl and methoxyl groups.

Particularly suitable groups R₃ for inclusion in the compounds of the formula (II), (IV) or (V) include the hydrogen, fluorine and chlorine atoms and the methyl, trifluoromethyl, allyl, nitro, amino, acetamido, allyloxyl and methoxysulphonylamino groups.

Particularly suitable groups R₄ for inclusion in the compounds of the formulae (I), (IV) or (V) include the hydrogen and chlorine atoms, the hydrogen atom being preferred.

Further suitable values for R₃ for inclusion in the compounds of the formulae (II), (IV) or (V) are (CH₂)_(n) OR₁₉, (CH₂)_(n) SR₁₉, (CH₂)_(n) SO₂ R₁₉, (CH₂)_(n) NHCOR₁₉, (CH₂)_(n) NHCO₂ R₁₉ and (CH₂)_(n) N(CH₃)COR₁₉ groups wherein n is 1, 2 or 3 and R₁₉ is a methyl or ethyl group.

Compounds having vasodilatory activity may be found within formula (VI): ##STR7## and salts thereof wherein R₁, R₂, R₅ and R₆ are as defined in relation to formula (I).

Most suitably, NR₁ R₂ is a cyclic group of sub-formula (b) as defined in relation to formula (II).

Most suitably, R₅ is a methyl or ethyl group and R₆ is a methyl or ethyl group.

Preferably R₅ and R₆ are both methyl groups.

Acid addition salts of the amino compounds of formulae (I) - (VI) may be made with acids in conventional manner. Suitable salt-forming acids include hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, p-toluenesulphonic, acetic, propionic, succinic, citric, tartaric, mandelic, lactic, gluconic or other pharmaceutically acceptable organic or inorganic acid.

The compounds of the invention exist in optically active forms. Those skilled in the chemical arts will realise that racemic mixtures of amino compounds can often be separated into pure optical isomers using such techniques as fractional crystallisation with optically active acids and the like.

The compounds of formula (I) may be prepared by the reaction of an amine of the formula NHR₁ R₂ with an epoxide of the formula (VII): ##STR8## wherein R₃, R₄, R₅ and R₆ are as defined in relation to formula (I).

The reaction of the amine and epoxide may be carried out at any non-extreme low, medium or high temperature (for example, -10° C to 200° C) but in general ambient or slightly elevated temperatures are most suitable (for example, 12° C to 100° C). The reaction is normally carried out in the presence of a solvent such as alkanolic or ketonic solvent (for example, methanol, ethanol, propanol, acetone or methylethylketone).

It has been found that the reaction frequently proceeds smoothly and efficiently if the reaction is carried out in warmed or refluxing ethanol.

The above reaction has been found to give a trans product substantially free from the cis-isomer.

Compounds of formula (I) wherein R₃ is an amino group or substituted amino group may also be prepared by reduction (and optionally thereafter acylation or sulphonation) of the corresponding compound in which R₃ is a nitro group. Similarly, hydroxyl groups may be alkylated by conventional methods under conventional conditions if desired.

Frequently, pure compounds of this invention prepared by the preceding method may form crystals which contain water of crystallisation, for example, from 1 to 4 molecules of water per compound of formula (I).

The useful intermediates of the formula (VII) may be prepared by the method of Livingstone, R.; (J. Chem. Soc., 76 (1962)).

This method is summarised by reaction sequence A. ##STR9## 

What we claim is:
 1. A pharmaceutical composition useful for effecting vasodilation in humans and animals which comprises a vasodilatory amount of a compound of the formulaor a pharmaceutically acceptable acid addition salt thereof wherein Nr₁ r₂ is a 3- to 8-membered heterocycle wherein the nitrogen atom is the only heteroatom, unsubstituted or substituted by 1 or 2 methyl groups; R⁵ is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; and R⁶ is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl, in combination with a pharmaceutically acceptable carrier.
 2. A composition according to claim 1 wherein NR₁ R₂ is a moiety of the formula ##STR10## wherein X is a bond joining the two carbon atoms, CH₂, CH₂ --CH₂, CH₂ --CH₂ --CH₂, or CH═CH;R₁₃ is hydrogen or methyl; and R₁₄ is hydrogen or methyl.
 3. A composition according to claim 1 wherein NR₁ R₂ is a pyrrolidyl, piperidyl, methylpyrrolidyl or hexamethyleneimino moiety.
 4. A composition according to claim 2 wherein R₅ and R₆ are each methyl or ethyl.
 5. A composition according to claim 2 wherein R₅ and R₆ are each methyl.
 6. A composition according to claim 3 wherein X is a bond joining the two carbon atoms, CH₂ or CH₂ --CH₂.
 7. A composition according to claim 1 wherein the compound is in the form of an acid addition salt wherein said salt is selected from the group consisting of the hydrochloride, hydrobromide, sulphate, phosphate, methane sulfonate, p-toluene sulfonate, acetate, propionate, succinate, citrate, tartrate, mandelate, lactate and gluconate.
 8. A composition according to claim 1 wherein the compound is trans 4-piperidino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 9. A composition according to claim 1 wherein the compound is trans-4-pyrrolidino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 10. A composition according to claim 1 wherein the compound is trans-4-[4-methylpiperidino]-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 11. A composition according to claim 1 wherein the compound is trans-4-hexamethylenimino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 12. A composition according to claim 1 wherein the compound is trans-4-heptamethylenimino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 13. A composition according to claim 1 wherein the compound is trans-4-[2,4-dimethylpyrrolidino]-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 14. A composition according to claim 1 wherein the compound is trans-4-pyrrolidino-3,4-dihydro-2,2-diethyl-2H-benzo[b]pyran-3-ol hydrochloride.
 15. A method of effecting vasodilation in humans and animals which comprises administering to a human or animal in need thereof a vasodilatory amount of a compound of the formula ##STR11## or a pharmaceutically acceptable acid addition salt thereof wherein NR₁ R₂ is a 3- to 8-membered heterocycle wherein the nitrogen atom is the only heteroatom, unsubstituted or substituted by 1 or 2 methyl groups;R₅ is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; and R₆ hydrogen, alkyl of 1 to 6 carbon atoms or phenyl, in combination with a pharmaceutically acceptable carrier.
 16. A method according to claim 15 wherein NR₁ R₂ is a moiety of the formula ##STR12## wherein X is a bond joining the two carbon atoms, CH₂, CH₂ --CH₂, CH₂ --CH₂ --CH₂, or CH═CH;R₁₃ is hydrogen or methyl; and R₁₄ is hydrogen or methyl.
 17. A method according to claim 15 wherein NR₁ R₂ is pyrrolidyl, piperidyl, methylpyrrolidyl or hexamethyleneimino moiety.
 18. A method according to claim 15 wherein R₅ and R₆ are each methyl or ethyl.
 19. A method according to claim 15 wherein R₅ and R₆ are each methyl.
 20. A method according to claim 15 wherein X is a bond joining the two carbon atoms, CH₂ or CH₂ --CH₂.
 21. A method according to claim 15 wherein the compound is in the form of an acid addition salt wherein said salt is selected from the group consisting of the hydrochloride, hydrobromide, sulphate, phosphate, methane sulfonate, p-toluene sulfonate, acetate, propionate, succinate, citrate, tartrate, mandelate, lactate and gluconate.
 22. A method according to claim 15 wherein the compound is trans-4-piperidino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 23. A method according to claim 15 wherein the compound is trans-4-pyrrolidino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 24. A method according to claim 15 wherein the compound is trans-4-[4-methylpiperidino]-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 25. A method according to claim 15 wherein the compound is trans-4-hexamethylenimino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 26. A method according to claim 15 wherein the compound is trans-4-heptamethylenimino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 27. A method according to claim 15 wherein the compound is trans-4-[2,4-dimethylpyrrolidino]-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol hydrochloride.
 28. A method according to claim 15 wherein the compound is trans-4-pyrrolidino-3,4-dihydro-2,2-diethyl-2H-benzo[b]pyran-3-ol hydrochloride. 